Khan B.A.,Translational Sciences, Inc.
Critical Care Medicine | Year: 2017
OBJECTIVES:: Delirium severity is independently associated with longer hospital stays, nursing home placement, and death in patients outside the ICU. Delirium severity in the ICU is not routinely measured because the available instruments are difficult to complete in critically ill patients. We designed our study to assess the reliability and validity of a new ICU delirium severity tool, the Confusion Assessment Method for the ICU-7 delirium severity scale. DESIGN:: Observational cohort study. SETTING:: Medical, surgical, and progressive ICUs of three academic hospitals. PATIENTS:: Five hundred eighteen adult (≥ 18 yr) patients. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Patients received the Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale, and Delirium Rating Scale-Revised-98 assessments. A 7-point scale (0–7) was derived from responses to the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale items. Confusion Assessment Method for the ICU-7 showed high internal consistency (Cronbach’s α = 0.85) and good correlation with Delirium Rating Scale-Revised-98 scores (correlation coefficient = 0.64). Known-groups validity was supported by the separation of mechanically ventilated and nonventilated assessments. Median Confusion Assessment Method for the ICU-7 scores demonstrated good predictive validity with higher odds (odds ratio = 1.47; 95% CI = 1.30–1.66) of in-hospital mortality and lower odds (odds ratio = 0.8; 95% CI = 0.72–0.9) of being discharged home after adjusting for age, race, gender, severity of illness, and chronic comorbidities. Higher Confusion Assessment Method for the ICU-7 scores were also associated with increased length of ICU stay (p = 0.001). CONCLUSIONS:: Our results suggest that Confusion Assessment Method for the ICU-7 is a valid and reliable delirium severity measure among ICU patients. Further research comparing it to other delirium severity measures, its use in delirium efficacy trials, and real-life implementation is needed to determine its role in research and clinical practice. Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
News Article | April 20, 2017
Mindfulness training may be one way to help students successfully transition to college life, according to Penn State researchers. The first semester of college is a time of great transition for many students -- they often are living away from home for the first time, have a much more fluid schedule than in high school and are potentially surrounded by a new peer group. For all of these reasons and more, this can be an incredibly stressful time in a student's life. To help ease this transition, researchers offered an eight-session mindfulness training program to first-year students at Penn State, according to Kamila Dvorakova, a doctoral Compassion and Caring fellow in the Edna Bennett Pierce Prevention Research Center and lead author of the study. In mindfulness meditation, practitioners learn how to develop an accepting, nonjudgmental and kind attitude toward present moment thoughts and feelings, according to the researchers, who presented their findings in a recent issue of the Journal of American College Health. At the end of the eight sessions, the intervention was associated with significant increases in the students' life satisfaction, as well as a significant decrease in depression and anxiety, when compared to students who did not participate in the training. There was also an overall drop in alcohol use between the students who took part in the mindfulness program and the control group. "We offered an experiential, practice-oriented training," said Dvorakova. "Rather than telling the students what to do, we had them explore and talk about how to be mindful in their daily lives and discover the benefits for themselves. We found that underneath the stress that students are experiencing is a deep desire to appreciate life and feel meaningful connections with other people. It is our responsibility as educators to create academic environments that nurture both students' minds and hearts." Dvorakova and Mark Agrusti, mindfulness and meditation integration specialist, Prevention Research Center, adapted the existing Learning to BREATHE program -- originally developed for adolescents by Patricia C. Broderick, research associate, Prevention Research Center -- for college students and called it Just BREATHE. The teachings in the eight sessions were themed around the BREATHE acronym: body, reflections, emotions (or awareness), attention, tenderness (or self-compassion), healthy habits and empowerment. "The beginning of the college career presents such a unique opportunity -- all of these students are going through this same transition at the same time," said Agrusti. "These freshmen are beginning to acquire habits and perceptions that will shape their lives as students and adults, so it's a perfect time for them to discover practices, such as mindfulness, stress management, self-care and emotional literacy skills." Fifty-two undergraduate students participated in the intervention, with another 53 serving as a control. The program included self-awareness practices, emotion-regulation skills and simple mindfulness techniques to help students manage stressful situations, the researchers said. The participants were also given cards and stickers for home practice to serve as reminders to use mindfulness techniques when they encounter stressful situations. The students indicated that the three most effective in-class exercises were three mindful breaths, breath awareness and mindfulness of emotions. A total of 98 percent of the participants would recommend the program to friends and classmates. According to the researchers, future studies might include adding more participants, scheduling long-term follow-ups and integrating mindfulness with academic lessons. The National Center for Advancing Translational Sciences, Clinical and Translational Science Institute, National Institute on Drug Abuse and the Edna Bennett Pierce Prevention Research Center supported this work. Also working on the study were: Moé Kishida, a doctoral candidate in kinesiology; Jacinda Li, a doctoral candidate in human development and family studies; Steriani Elavsky, former assistant professor of kinesiology; Mark T. Greenberg, Edna Bennett Pierce Endowed Chair in Prevention Research and professor of human development and psychology, all of Penn State.
News Article | May 4, 2017
Glaucoma, a leading cause of blindness worldwide, most often is diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, there's no way to accurately predict which patients might lose vision most rapidly. Now, studying mice, rats and fluid removed from the eyes of patients with glaucoma, researchers at Washington University School of Medicine in St. Louis have identified a marker of damage to cells in the eye that potentially could be used to monitor progression of the disease and the effectiveness of treatment. The findings are published online May 4 in the journal JCI Insight. "There hasn't been a reliable way to predict which patients with glaucoma have a high risk of rapid vision loss," said principal investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. "But we've identified a biomarker that seems to correlate with disease severity in patients, and what that marker is measuring is stress to the cells rather than cell death. Other glaucoma tests are measuring cell death, which is not reversible, but if we can identify when cells are under stress, then there's the potential to save those cells to preserve vision." Glaucoma is the second-leading cause of blindness in the world, affecting more than 60 million people. The disease often begins silently, with peripheral vision loss that occurs so gradually that it can go unnoticed. Over time, central vision becomes affected, which can mean substantial damage already has occurred before any aggressive therapy begins. Many patients start receiving treatment when their doctors discover they have elevated pressure in the eye. Those treatments, such as eye drops, are aimed at lowering pressure in the eye, but such therapies may not always protect ganglion cells in the retina, which are the cells destroyed in glaucoma, leading to vision loss. Apte, also a professor of developmental biology, of medicine and of neuroscience, said that all current treatments for glaucoma are aimed at lowering pressure in the eye to reduce ganglion cell loss and not necessarily at directly preserving ganglion cells. Glaucoma specialists attempt to track the vision loss caused by ganglion cell death with visual field testing. That's when a patient pushes a button when they see a blinking light. As vision is lost, patients see fewer lights blinking in the periphery of the visual field, but such testing is not always completely reliable, according to the paper's first author, Norimitsu Ban, MD, an ophthalmologist and a postdoctoral research associate in Apte's laboratory. Some older people don't do as well on the visual field test for reasons that may not be related to what's going on in their eyes, Ban explained. He said that finding a marker of cell damage in the eye would be a much more reliable way to track the progression of glaucoma. "We were lucky to be able to identify a gene and are very excited that the same gene seems to be a marker of stress to ganglion cells in the retinas of mice, rats and humans," Ban said. Studying mouse models of glaucoma, Ban, Apte and their colleagues identified a molecule in the eye called growth differentiation factor 15 (GDF15), noting that the levels of the molecule increased as the animals aged and developed optic nerve damage. When they repeated the experiments in rats, they replicated their results. Further, in patients undergoing eye surgery to treat glaucoma, cataracts and other issues, the researchers found that those with glaucoma also had elevated GDF15 in the fluid of their eyes. "That was exciting because comparing the fluid from patients without glaucoma to those with glaucoma, the GDF15 biomarker was significantly elevated in the glaucoma patients," Apte said. "We also found that higher levels of the molecule were associated with worse functional outcomes, so this biomarker seems to correlate with disease severity." Apte and Ban don't believe that the molecule causes cells in the retina to die; rather, that it is a marker of stress in retinal cells. "It seems to be a harbinger of future cell death rather than a molecule that's actually damaging the cells," Apte said. A potential limitation of this study is that the fluid samples were taken from the eyes of patients only once, so it was not possible to monitor levels of GDF15 over time. In future studies, it will be important to measure the biomarker at several time points to determine whether levels of the biomarker increase as the disease progresses, Apte said. He also would like to learn whether GDF15 levels eventually decline in those who have significant vision loss from glaucoma. In theory, Apte said, when most of the ganglion cells in the retina already have died, fewer cells would be under stress, and that could mean lower levels. "So we are interested in doing a prospective study and sampling fluid from the eye over several months or years to correlate glaucoma progression with levels of this marker," he said. "We'd also like to learn whether levels of GDF15 change after treatment, a particularly important question as we try to develop therapies that preserve vision more effectively in these patients." Ban N, Siegfried CJ, Lin JB, Shiu YB, Sein J, Pita-Thomas W, Sene A, Santeford A, Gordon M, Lamb R, Dong Z, Kelly SC, Cavalli V, Yoshino J, Apte RS. GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight. May 4, 2017. This work was supported by the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke and the National Institute of General Medical Sciences, of the National Institutes of Health (NIH), grant numbers R01 EY019287, UL1 KL2TR000450, P30 DK56341, P30 DK02057, DK104995, R01 EY021515, R01 DE0220000, R01 NS0824446, P30 EY02687, T32 GM007200, UL1 TR000448 and TL1 TR000449. Additional funding provided by the Schulak Family Gift Fund for Retinal Research, the Jeffrey Fort Innovation Fund, the Kuzma Family Gift Fund, the Central Society for Clinical and Translational Research, a Research to Prevent Blindness Scientist Award, the Washington University Institute of Clinical and Translational Sciences, the American Federation for Aging Research, the Vitreoretinal Surgery Foundation and an unrestricted grant from Research to Prevent Blindness Inc. Washington University's Office of Technology Management has filed intellectual property applications based on these studies in which the authors Rajendra S. Apte and Jun Yoshino are listed as inventors. Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
News Article | April 17, 2017
When scientists with the pharmaceutical company Pfizer started clinical trials in 1991 on a chemical compound named UK-92480, they aimed to show the drug’s potential therapeutic benefit for a cardiovascular condition caused by restricted blood flow to the heart muscle. Less than two years later, hope that the compound, now better known as sildenafil, could treat angina began to fade. But the drug wasn’t shelved. Rather, scientists began exploring whether one of the drug’s reported side effects—erections—could help men suffering from another condition. The U.S. Food and Drug Administration in 1998 approved sildenafil, under the brand name Viagra, for the treatment of erectile dysfunction. In its first year on the market, sales of the little blue pill topped $1 billion. The transformation of sildenafil into a treatment that’s now been prescribed to tens of millions of men around the world is one of the most well-known examples of a practice known as drug repurposing. The practice isn’t new but it is becoming an increasingly attractive option for academic and pharmaceutical industry researchers, as well as nonprofit organizations and patient advocacy groups—all of whom are seeking ways to cut the time and expense involved in getting new treatments to market. Winning approval for a new drug takes about 14 years on average and costs can exceed $2 billion, according to data from the National Center for Advancing Translational Sciences, or NCATS. The failure rate in the drug development process, meanwhile, is 95 percent. That leaves a vast pool of partially developed chemical compounds that could potentially be tapped for uses other than which they were originally intended. Those repurposed drugs could move to market in less time and for less money than it takes to gain approval for novel drugs by skipping preclinical testing requirements and, possibly, Phase 1 safety and dosing trials. The ability to bypass those stages means a repurposed drug could make it to market in only four years and at a fraction of the cost of a brand new treatment, according to Cures Within Reach. The Illinois-based nonprofit group, which supports medical repurposing research, also notes that the “risks are better known and the chance of failure due to adverse side effects is reduced” with repurposed drugs. While serendipity has largely driven the repurposing of drugs in the past, more deliberate approaches to this practice have been recently developed in a bid to fuel more collaboration between stakeholders and hasten the development of new therapies. A collapsed timeline In 2012, NCATS, an arm of the National Institutes of Health, launched a program called Discovering New Therapeutic Uses for Existing Molecules that makes proprietary drugs that have undergone significant research and development by pharmaceutical companies available to academic researchers. Christine Colvis, the director of drug development partnership programs for NCATS, called drug repurposing “a viable strategy for developing new therapies” and one that is generating more interest and engagement from academic institutions and academic investigators. “There are so many diseases for which there are no treatments or for which current treatments are not adequate or don’t treat all of the patient population,” Colvis, whose team leads the New Therapeutic Uses program, said. “There is just so much unmet medical need out there and when there’s something for a scientist, for a researcher, that’s sort of staring them in the face as a potential thing that could make a difference in people’s lives, it’s hard for them not to pursue that path.” Colvis pointed to research by neurologist Stephen Strittmatter of Yale University as one promising example of collaboration between academia and industry that NCATS is supporting. Strittmatter and his colleagues in 2012 published a paper that suggested blocking a protein called Fyn kinase may help treat Alzheimer’s disease. Those findings were released around the same time NCATS launched its New Therapeutic Uses program and made a Fyn kinase inhibitor developed by AstraZeneca available to researchers. AstraZeneca had developed the drug, called saracatinib, to treat cancer. Strittmatter and his colleagues submitted a proposal to test saracatinib as a treatment for Alzheimer’s-related brain abnormalities and received one of the first New Therapeutic Uses awards in June 2013. The research team was able to begin a Phase 2a human clinical trial of saracatinib within about 18 months, compared to the decade it can take to move a new treatment to that stage. “Had AstraZeneca not put that drug on our list of drugs that would be available, we still wouldn’t be investigating this as a potential target for Alzheimer’s disease, and had Dr. Strittmatter not published his paper or had he not seen our funding opportunity announcement, still nothing would be happening,” Colvis said. “But instead now we are in the final year of a Phase 2 trial and hope to see those results in about a year from now.” Partnerships NCATS, in collaboration with AstraZeneca and Janssen Research & Development, LLC, in February announced it was offering $6 million in funding to support additional public-private partnerships between the biomedical research community and pharmaceutical companies. Other NCATS partners for this program include AstraZeneca subsidiary MedImmune, AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Pfizer and Sanofi. Colvis said the types of partnerships NCATS is helping foster are “really just trying to demonstrate a strategy. Our real hope is that other entities start to use this model and this strategy.” “We hope to see this model used around the world in order to really have an impact on health,” she said. While Colvis describes NCATS’ efforts to promote drug repurposing as “disease agnostic,” other groups are embracing the practice in an attempt to find treatments for a specific group of conditions: rare diseases. Findacure, a charity based in Cambridge, England, is working to develop a model to support repurposing existing, generic drugs to help treat patients suffering from conditions that affect fewer than 1 in 2,000 people. (In the United States, a rare disease is defined as a condition affecting fewer than 200,000 people at any given time). “It’s a type of research that can be delivered more cheaply and more quickly and that’s really important in the rare disease space,” said Rick Thompson, Findacure’s head of research. Of the more than 7,000 rare diseases, only around 400 have licensed treatments, according to Findacure. Thompson said it’s difficult for the pharmaceutical industry to actively repurpose generic drugs for rare diseases for two reasons: a lack of profitability due to the small patient population and the difficulty to secure intellectual property. Findacure has developed a new mechanism called the Rare Disease Drug Repurposing Social Impact Bond in an effort to address that gap. The model, which Findacure has been working with Cures Within Reach to develop, would use money the National Health Services in the U.K. saves by treating patients who have rare diseases with repurposed, generic drugs to reimburse the cost of clinical trials that prove the effect of such drugs. “It’s securing returns based on money that’s been saved rather than delivering a high drug price,” Thompson said. The charity has completed a proof of concept study for its model and is now working toward developing a full business plan. Meanwhile, the group recently launched an open call for drug repurposing ideas for rare diseases in partnership with Cures Within Reach and Healx of Cambridge, England. The open call project aims to “demonstrate the huge potential of clinic-led, patient group-led, and researcher-driven innovation in drug repurposing for rare diseases” and show “the need for new funding streams to help these ideas bridge the translational gap,” like Findacure’s Rare Disease Drug Repurposing Social impact Bond. “We think this has real potential to promote and allow this type of generic drug repurposing in the rare disease space to move forward,” Thompson said. “We need some kind of innovation in this space to encourage this type of work.”
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 1.52M | Year: 2012
DESCRIPTION (provided by applicant): Each year, as many as 2 million Americans develop venous thromboembolism (VTE). VTEs are blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). It is estimated that 10-20% of VTEpatients die, and the annual direct costs are up to 10 billion. Despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains the most commonly used treatment for venous thromboembolism. The drawbacks of anticoagulation include the following: 1) it does not dissolve existing clots or thrombi; 2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores); 3) it is linked to recurrent venous thromboembolism in up to 30% of patients; 4) it has significant bleeding risk; and 5) it has never been shown to save lives in a randomized clinical trial. Tissue plasminogen activator (TPA) and other blood clot-dissolving drugs are better at preventing post-thrombotic symptoms, but the high doses used are: 1)only partially successful at dissolving blood clots; 2) significantly increase bleeding risks and, 3) do not reduce mortality. It is clear that there is a need for a safer, more-effective therapy that savs lives, reduces disability, and lowers health carecosts associated with venous thromboembolism. Through our successful completion of the Phase I portion of this multi-phase STTR study, we (Translational Sciences, Inc. [TSI]) have discovered a molecule that dissolves blood clots through a unique mechanism-inactivating the major inhibitor of plasmin. Through synergism, this molecule increases the potency and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. TSI's extensive pre- clinical studies indicate that this novel approach could substantially reduce the morbidity, mortality and costs associated with VTE. In our Phase I STTR feasibility studies, we successfully converted this molecule, following FDA guidance, into a clot-dissolving biologic therapeutic (Lysimab) suitable for investigation in clinical trials. The Phase II STTR goal is to significantly advance Lysimab toward human trials by: 1) determining optimal (safe/effective) therapeutic dose combinations of Lysimab and TPA in vivo in a humanized model of pulmonary embolism;2) producing and purifying 10 g of Lysimab under GMP conditions, 3) investigating the tissue binding, safety, pharmacokinetics and pharmacodynamics of Lysimab, and 4) submitting an IND to the FDA. This work will be carried out with TSI's Phase II STTR partner, the University of Wisconsin. We will leverage our substantial pre-clinical data to form a strategic alliance with a big pharma partner with the clinical, regulatory and financial resources needed to conduct clinical trials for FDA approval of Lysimab.We project that a combination TPA/a2AP-I therapy could lead to the survival of an additional 17,000-36,000 patients per year and gt50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase II project and transferof commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to heart and stroke victims. PUBLIC HEALTH RELEVANCE: Each year, as many as 2 million Americans develop venousthromboembolism (VTE), and the annual direct costs are up to 10 billion. Yet, despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains widely used for VTE treatment despite the fact that it does not dissolve clots, itis associated with serious side-effects and, it has never been shown to save lives in a randomized clinical trial. This multi- phase STTR project seeks to develop a novel VTE therapy that could markedly reduce death, disability, and billions of dollars indirect and indirect VTE-related costs.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2012
DESCRIPTION (provided by applicant): Stroke is the 3rd leading cause of death and the primary cause of severe, long term disability. Each year 795,000 Americans have a stroke and the annual costs to the economy are 57.9 billion. The vast majority of acute ischemic strokes are caused by a thrombus (blood clot) which occludes the blood vessel and stops blood flow to the brain. Tissue plasminogen activator (TPA), an agent that catalyzes the dissolution of blood clots, is the only effective, FDA-approved treatment for ischemic stroke. Unfortunately, TPA is associated with significant risks, delays in treatment, and is unsuccessful in up to 70% of patients at dissolving blood clots in sufficient time to protect the brain. There is a need for a safer, more effective therapy that facilitates early treatment, saves lives, reduces disability and lowers health care costs. In pre-clinical studies, we have shown that these goals might be achieved by a molecule that inactivates the major inhibitor of plasmin and, dissolves clots through a unique mechanism that avoids the risk of hemorrhage and neurotoxicity associated with TPA therapy. Following FDA guidance, we converted this molecule into a biologic drug candidate for stroke (stromab) that potently accelerates the dissolution of human clots. The goal of this Fast Track application is to move stromab further towards human trials by following FDA guidance to: 1) determine the optimal formulation and therapeutic time window for treatment, 2) produce and purify stromab under GLP conditions, 3) investigate the safety, pharmacokinetics and pharmacodynamics of stromab and, 4) submit an IND to the FDA.
Translational Sciences, Inc. | Date: 2015-10-01
Methods for increasing plasmin activity in a patient in need thereof are provided, comprising administering to the patient a therapeutic amount of an agent which binds to 2-antiplasmin at a binding site to increase conversion of 2-antiplasmin from an inhibitor to a plasmin substrate, thereby increasing plasmin activity in the patient. Also provided are methods for the identification of compounds or molecules that increase plasmin activity, comprising determining whether the compound or molecule binds to a binding site on 2-antiplasmin which increases the conversion of 2-antiplasmin from an inhibitor to a plasmin substrate, wherein the compound or molecule is not an antibody, thereby identifying a compound or molecule which increases plasmin activity. Further provided are pharmaceutical compositions and methods of use thereof for the treatment of myocardial infarction, thrombosis, ischemic stroke, and pulmonary embolism.
Translational Sciences, Inc. | Date: 2014-03-06
Compositions and methods of using SerpinF2-binding molecules for preventing and/or reducing organ damage, functional disability or mortality in a patient at risk due to the activity of SerpinF2 and/or plasminogen activators on tissue injury. Also provided are compositions and methods of using SerpinF2-binding molecules for inhibiting hemorrhage, edema, and apoptosis. Methods for the preparation of medicaments for such methods of treatment and prevention are provided.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2015
DESCRIPTION provided by applicant Each year venous thromboembolism VTE affects up to million Americans and million people worldwide VTE patients have blood clots in the legs venous thrombosis that may travel to the lungs pulmonary embolism Up to of VTE patients die and the annual direct U S healthcare costs are $ billion For more than years anticoagulation has been the standard therapy for VTE Anticoagulation has many drawbacks it does not dissolve existing thrombi up to of patients develop post thrombotic symptoms pain swelling chronic sores up to of patients develop chronic thromboembolic pulmonary hypertension a severe cardiopulmonary disease it is linked to VTE recurrence in up to of patients it has significant bleeding risk and it has not been proven to save lives in a randomized clinical trial High doses of tissue plasminogen activator TPA like agents may prevent post thrombotic complications by dissolving clots but they are only partially successful cause bleeding and do not reduce mortality There is a need for a safer more effective therapy for VTE that saves lives reduces disability and lowers health care costs We Translational Sciences Inc TSI successfully completed a Phase I II STTR in which we discovered and developed a therapeutic antibody Lysimab that dissolves blood clots through a unique mechanism Through synergism Lysimab increases the potency safety and specificity of TPA and it avoids TPA related hemorrhage and neurotoxicity Following FDA recommendations in Phase I studies we successfully developed Lysimab into a stable clot dissolving therapeutic suitable for clinical trials Our Phase II STTR advanced Lysimab through preclinical studies toward human trials by demonstrating safe effective synergistic therapeutic dose combinations of Lysimab and TPA in vivo in a humanized pulmonary embolism model producing and purifying Lysimab under GLP conditions characterizing Lysimabandapos s human tissue binding char acteristics demonstrating Lysimabandapos s remarkable safety profile and pharmacokinetics in pivotal safety toxicology studies in a pharmacologically relevant species completing a successful FDA pre IND meeting raising strategic investment funds for clinical development and securing competitive selection by the NIH SMARTT regulatory team for FDA IND submission Building on this progress this Phase IIb proposal aims to complete a first in human Phase I study of the safety pharmacokinetics pharmacodynamics and biomarker efficacy of Lysimab Then we will leverage our pre clinical clinical data to form a strategic alliance with a Pharmaceutical partner to conduct later phase clinical trials for FDA approval of Lysimab We project that combination TPA Lysimab therapy could lead to the survival of an additional patients per year and a andgt reduction in post thrombotic symptoms and their associated costs Upon completion of this Phase IIb project and transfer of commercialization responsibilities to our strategic partner TSI will investigate the potential benefits of this platform technology to other patients with thrombotc diseases PUBLIC HEALTH RELEVANCE Venous thromboembolism affects about million people per year worldwide costing as much as $ billion per year in the U S alone Anticoagulation therapy is the standard of care for patients with venous thromboembolism but anticoagulation has serious risks and in more than of patients anticoagulation fails to prevent complications that lead to recurrent venous thromboembolism chronic pain and disability This Phase IIb proposal seeks to develop a novel therapy for venous thromboembolism that could markedly reduce death disability and healthcare costs
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2011
DESCRIPTION (provided by applicant): Stroke is the 3rd leading cause of death and the primary cause of severe, long term disability. Each year 795,000 Americans have a stroke and the annual costs to the economy are 57.9 billion. The vast majority of acute ischemic strokes are caused by a thrombus (blood clot) which occludes the blood vessel and stops blood flow to the brain. Tissue plasminogen activator (TPA), an agent that catalyzes the dissolution of blood clots, is the only effective, FDA-approved treatment for ischemic stroke. Unfortunately, TPA is associated with significant risks, delays in treatment, and is unsuccessful in up to 70% of patients at dissolving blood clots in sufficient time to protect the brain. There is a need for a safer, more effective therapy that facilitates early treatment, saves lives, reduces disability and lowers health care costs. In pre-clinical studies, we have shown that these goals might be achieved by a molecule that inactivates the major inhibitor of plasmin and, dissolves clots through a unique mechanism that avoids the risk of hemorrhage and neurotoxicity associated with TPA therapy. Following FDA guidance, we converted this molecule into a biologic drug candidate for stroke (stromab) that potently accelerates the dissolution of human clots. The goal of this Fast Track application is to move stromab further towards human trials by following FDA guidance to: 1) determine the optimal formulation and therapeutic time window for treatment, 2) produce and purify stromab under GLP conditions, 3) investigate the safety, pharmacokinetics and pharmacodynamics of stromab and, 4) submit an IND to the FDA. PUBLIC HEALTH RELEVANCE: Each year 795,000 Americans have a stroke and the annual costs to the economy are 57.9 billion. Tissue plasminogen activator, the only approved treatment for ischemic stroke, is associated with significant risks, delays in treatment, and is unsuccessful in up to 70% of patients at dissolving blood clots in sufficient time to protect the brain. Thisproject seeks to develop a novel therapy for stroke that could markedly reduce death, disability and costs.